Biology subjects

Sharifi, K. A.

Publications and source records attributed to Sharifi, K. A..

4 recordsLinked to original sources

bioRxiv2024

Focused Ultrasound Impels the Delivery and Penetration of Model Therapeutics into Cerebral Cavernous Malformations

BACKGROUNDCerebral cavernous malformations (CCMs) are vascular neoplasms in the brain that can cause debilitating symptoms. Current treatments pose significant risks to some patients, motivating the development of new nonsurgical options. We recently discovered that focused ultrasound-microbubble treatment (FUS) arrests CCM formation and growth. Here, we build on this discovery and assess the ability of FUS to deliver model therapeutics into CCMs. METHODSQuantitative T1 mapping MRI sequences were used with 1 kDa (MultiHance; MH) and 17 kDa (GadoSpin D; GDS) contrast agents to assess the FUS-mediated delivery and penetration of model small molecule drugs and biologics, respectively, into CCMs of Krit1 mutant mice. RESULTSFUS elevated the rate of MH delivery to both the lesion core (4.6-fold) and perilesional space (6.7-fold). Total MH delivery more than doubled in the lesion core and tripled in the perilesional space when FUS was applied immediately prior to MH injection. For the model biologic drug (i.e. GDS), FUS was of greater relative benefit, resulting in 21.7-fold and 3.8-fold delivery increases to the intralesional and perilesional spaces, respectively CONCLUSIONSFUS augments the delivery and penetration of therapeutics into the complex and disorganized CCM microenvironment. Benefits to small molecule drug delivery are more evident in the perilesional space, while benefits to biologic delivery are more evident in CCM cores. These findings, when combined with ability of FUS alone to control CCMs, highlight the potential of FUS to serve as a powerful non-invasive therapeutic platform for CCM.

bioengineering↗

bioRxiv2024

Focused Ultrasound Blood-Brain Barrier Opening Arrests the Growth and Formation of Cerebral Cavernous Malformations

BACKGROUNDCerebral cavernous malformations (CCM) are vascular lesions within the central nervous system, consisting of dilated and hemorrhage-prone capillaries. CCMs can cause debilitating neurological symptoms, and surgical excision or stereotactic radiosurgery are the only current treatment options. Meanwhile, transient blood-brain barrier opening (BBBO) with focused ultrasound (FUS) and microbubbles is now understood to exert potentially beneficial bioeffects, such as stimulation of neurogenesis and clearance of amyloid-{beta}. Here, we tested whether FUS BBBO could be deployed therapeutically to control CCM formation and progression in a clinically-representative murine model. METHODSCCMs were induced in mice by postnatal, endothelial-specific Krit1 ablation. FUS was applied for BBBO with fixed peak-negative pressures (PNPs; 0.2-0.6 MPa) or passive cavitation detection-modulated PNPs. Magnetic resonance imaging (MRI) was used to target FUS treatments, evaluate safety, and measure longitudinal changes in CCM growth after BBBO. RESULTSFUS BBBO elicited gadolinium accumulation primarily at the perilesional boundaries of CCMs, rather than lesion cores. Passive cavitation detection and gadolinium contrast enhancement were comparable in CCM and wild-type mice, indicating that Krit1 ablation does not confer differential sensitivity to FUS BBBO. Acutely, CCMs exposed to FUS BBBO remained structurally stable, with no signs of hemorrhage. Longitudinal MRI revealed that FUS BBBO halted the growth of 94% of CCMs treated in the study. At 1 month, FUS BBBO-treated lesions lost, on average, 9% of their pre-sonication volume. In contrast, non-sonicated control lesions grew to 670% of their initial volume. Lesion control with FUS BBBO was accompanied by a marked reduction in the area and mesenchymal appearance of Krit mutant endothelium. Strikingly, in mice receiving multiple BBBO treatments with fixed PNPs, de novo CCM formation was significantly reduced by 81%. Mock treatment plans on MRIs of patients with surgically inaccessible lesions revealed their lesions are amenable to FUS BBBO with current clinical technology. CONCLUSIONSOur results establish FUS BBBO as a novel, non-invasive modality that can safely arrest murine CCM growth and prevent their de novo formation. As an incisionless, MR image-guided therapy with the ability to target eloquent brain locations, FUS BBBO offers an unparalleled potential to revolutionize the therapeutic experience and enhance the accessibility of treatments for CCM patients.

bioengineering↗

bioRxiv2023

Dynamics of Adult Axin2 Cell Lineage Integration in Granule Neurons of the Dentate Gyrus

The Wnt pathway plays critical roles in neurogenesis. The expression of Axin2 is induced by Wnt/{beta}-catenin signaling, making this gene a sensitive indicator of canonical Wnt activity. We employed pulse-chase genetic lineage tracing with the Axin2-CreERT2 allele to follow the fate of Axin2-positive cells in the adult hippocampal formation. We found Axin2 expressed in astrocytes, neurons and endothelial cells, as well as in the choroid plexus epithelia. Simultaneously with tamoxifen induction of Axin2 fate mapping, the dividing cells were marked with 5-ethynyl-2-deoxyuridine (EdU). Tamoxifen induction resulted in significant increase of dentate gyrus granule cells three months later; however, none of these neurons contained EdU signal. Conversely, six months after the tamoxifen/EdU pulse-chase labeling, EdU-positive granule neurons were identified in each animal. Our data imply that Axin2 is expressed at several different stages of adult granule neuron differentiation and suggest that the process of integration of the adult-born neurons from certain cell lineages may take longer than previously thought.

neuroscience↗

bioRxiv2022

Understanding Lesion Progression in a Chronic Model of Cerebral Cavernous Malformations through Combined MRI and Histology

Cerebral cavernous malformations (CCM), also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurologic deficits, while others have no symptoms. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. To address this problem, we have established a chronic mouse model of CCM, induced by postnatal ablation of Krit1 with Pdgfb-CreERT. These mice develop CCM lesions gradually over 4-6 months of age throughout of the brain. We examined lesion progression in these mice with T2-weighted 7T MRI protocols. Precise volumetric analysis of individual lesions revealed non-monotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and accelerated after about 3 months. Next, we established a modified protocol for dynamic contrast enhanced (DCE) MR imaging and produced quantitative maps of gadolinium tracer MultiHance in the lesions, indicating a high degree of heterogeneity in lesional permeability. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial cells, astrocytes, and microglia revealed that increased cell density surrounding lesions correlates with stability, while increased vasculature within and surrounding lesions may correlate with instability. Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive pre-clinical platform for testing new drug and gene therapies for controlling CCM.

neuroscience↗